Peripherally-selective inhibitors of dopamine-β-hydroxylase and method of their preparation

ABSTRACT

Compounds of formula I: 
                         
where R 1 , R 2  and R 3  are the same or different and signify hydrogens, halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4  signifies hydrogen, alkyl or alkylaryl group; X is CH 2 , O or S, and n is 1, 2 or 3, with the proviso that if X is CH 2 , n is not 1, and a method for their preparation. The compounds have potentially valuable pharmaceutical properties for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to peripherally-selective inhibitors ofdopamine-β-hydroxylase and a method of their preparation.

2. Description of Related Art

In recent years, interest in the development of inhibitors ofdopamine-β-hydroxylase (DβH) has centred on the hypothesis thatinhibition of this enzyme may provide significant clinical improvementsin patients suffering from cardiovascular disorders such as hypertensionor chronic heart failure. The rationale for the use of DβH inhibitors isbased on their capacity to inhibit the biosynthesis of noradrenaline,which is achieved via enzymatic hydroxylation of dopamine. Activation ofneurohumoral systems, chiefly the sympathetic nervous system, is theprincipal clinical manifestation of congestive heart failure (Parmley,W. W., Clinical Cardiology, 18: 440–445, 1995). Congestive heart failurepatients have elevated concentrations of plasma noradrenaline (Levine,T. B. et al., Am. J. Cardiol., 49:1659–1666, 1982), increased centralsympathetic outflow (Leimbach, W. N. et al., Circulation, 73: 913–919,1986) and augmented cardiorenal noradrenaline spillover (Hasking, G. J.et al., Circulation, 73:615–621, 1966). Prolonged and excessive exposureof myocardium to noradrenaline may lead to down-regulation of cardiacβ₁-adrenoceptors, remodelling of the left ventricle, arrhytmias andnecrosis, all of which can diminish the functional integrity of theheart. Congestive heart failure patients who have high plasmaconcentrations of noradrenaline also have the most unfavourablelong-term prognosis (Cohn, J. N. et al., N. Engl. J. Med., 311:819–823,1984). Of greater significance is the observation that plasmanoradrenaline concentrations are already elevated in asymptomaticpatients with no overt heart failure and can predict ensuing mortalityand morbidity (Benedict, C. R. et al., Circulation, 94:690–697, 1996).This implies that the activated sympathetic drive is not merely aclinical marker of congestive heart failure, but may contribute toprogressive worsening of the disease.

Inhibition of sympathetic nerve function with adrenoceptor antagonistsappeared a promising approach, however a significant proportion ofpatients do not tolerate the immediate haemodynamic deterioration thataccompanies β-blocker treatment (Pfeffer, M. A. et al., N. Engl. J.Med., 334:1396–7, 1996). An alternative strategy for directly modulatingsympathetic nerve function is to reduce the biosynthesis ofnoradrenaline via inhibition of DβH, the enzyme responsible forconversion of dopamine to noradrenaline in sympathetic nerves. Thisapproach has several merits including gradual modulation as opposed toabrupt inhibition of the sympathetic system, and causing increasedrelease of dopamine, which can improve renal function such as renalvasodilation, diuresis and natriuresis. Therefore inhibitors of DβH mayprovide significant advantages over conventional β-blockers.

Several inhibitors of DβH have been thus far reported in the literature.Early first and second generation examples such as disulfiram(Goldstein, M. et al., Life Sci., 3:763, 1964) anddiethyldithiocarbamate (Lippmann, W. et al., Biochem. Pharmacol., 18:2507, 1969) or fusaric acid (Hidaka, H. Nature, 231, 1971) and aromaticor alkyl thioureas (Johnson, G. A. et al, J. Pharmacol. Exp. Ther., 171:80, 1970) were found to be of low potency, exhibited poor selectivityfor DβH and caused toxic side effects. The third generation of DβHinhibitors however, were found to have much greater potency, such as forexample, nepicastat (RS-25560-197, IC₅₀ 9 nM) (Stanley, W. C., et al.,Br. J Pharmacol., 121: 1803–1809, 1997), which was developed to earlyclinical trials. Although devoid of some of the problems associated withfirst and second generation DβH inhibitors, a very important discoverywas that nepicastat was found to cross the blood brain barrier (BBB),thereby able to cause central as well as peripheral effects, a situationwhich could lead to undesired and potentially serious CNS side-effectsof the drug. Therefore there yet remains an unfulfilled clinicalrequirement for a potent, non-toxic and peripherally selective inhibitorof DβH, which could be used for treatment of certain cardiovasculardisorders. A DβH inhibitor with similar or even greater potency thannepicastat, but devoid of CNS effects (inability to cross the BBB) wouldprovide a significant improvement over all DβH inhibitor compounds thusfar described in the prior art.

BRIEF SUMMARY OF THE INVENTION

We have surprisingly found that incorporation of certain heteroatoms tothe carbocyclic ring and/or elongation of the amino alkyl side-chain ofthe nepicastat core-structure gives rise to a series of compoundspossessing significant and pronounced effects of potential usefulnessfor DβH inhibition. Many of these compounds are endowed with greaterpotency and significantly reduced brain access, giving rise to potentand peripherally selective DβH inhibitors. Thus, the invention relatesto compounds of general formula I;

where R₁, R₂ and R₃ are the same or different and signify hydrogens,halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino,alkylcarbonylamino, alkylamino or dialkylamino group; R₄ signifieshydrogen, alkyl or alkylaryl group; X signifies CH₂, oxygen atom orsulphur atom; n is 1, 2 or 3, with the proviso that when n is 1, X isnot CH₂; and the individual (R)- and (S)-enantiomers or mixtures ofenantiomers; and the pharmaceutically acceptable salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing a time-dependent decrease of noradrenalinelevels in the left ventricle of mice treated orally with a compoundaccording to the invention as compared to a reference standard.

FIG. 2 is two graphs showing noradrenaline levels in the left ventricleand brain parietal cortex of mice after oral administration of acompound according to the invention as compared to a reference standard.

FIG. 3 is four graphs showing noradrenaline levels in the heart andbrain of a rat after oral administration of a compound according to theinvention as compared to a reference standard.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds of general formula I;

where R₁, R₂ and R₃ are the same or different and signify hydrogens,halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino,alkylcarbonylamino, alkylamino or dialkylamino group; R₄ signifieshydrogen, alkyl or alkylaryl group; X signifies CH₂, oxygen atom orsulphur atom; n is 1, 2 or 3, with the proviso that when n is 1, X isnot CH₂; and the individual (R)- and (S)-enantiomers or mixtures ofenantiomers; and the pharmaceutically acceptable salts thereof.

Unless stated otherwise, in this specification the term alkyl (whetherused on its own or used in combination with other moieties) meanshydrocarbon chains, straight or branched, containing from one to sixcarbon atoms, optionally substituted by aryl, alkoxy, halogen,alkoxycarbonyl or hydroxycarbonyl groups; the term aryl (whether used onits own or used in combination with other moieties) means a phenyl ornaphthyl group, optionally substituted by alkyloxy, halogen or nitrogroup; and the term halogen means fluorine, chlorine, bromine or iodine.

Another aspect of the present invention is a process for the preparationof compounds of formula I. Some compounds according to formula II whereX signifies methylene (CH₂), oxygen or sulphur are known (Martinez, G.R. et al., U.S. Pat. No. 5,538,988, Jul. 23, 1996; Eriksson, M., PCTInt. Appl. WO 9959988A1, 25 Nov. 1999; Napoletano, M., PCT Int. Appl. WO9608489A1, 21 Mar. 1996; Sarda, N. et al., Tetrahedron Lett.,17:271–272, 1976; Neirabeyeh, M. Al et al., Eur. J. Med. Chem.,26:497–504, 1991) in the literature and others can be prepared by thoseskilled in the art. Compounds according to formula II are chiral, andformula II is therefore to be taken to represent both optically pureindividual (R)- and (S)-enantiomers or mixtures of enantiomers;

Compounds of formula I are prepared by reacting a compound of formula IIwhere X is CH₂, oxygen or sulphur; R₁, R₂ and R₃ are the same ordifferent and signify hydrogens, halogens, alkyl, alkylaryl, alkyloxy,hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino groupwith a compound of formula III:

where n signifies 1, 2 or 3; when n is 1 or 2, R₄ signifies hydrogen,alkyl or alkylaryl group; R₅ signifies a hydroxyl protecting group andR₆ signifies an amino protecting group; when n signifies 3, R₅ isdefined as above but R₄ and R₆ taken together represent a phthalimidogroup; and with a water soluble thiocyanate salt in an inert organicsolvent and in the presence of an organic acid, wherein the watersoluble thiocyanate salt is an alkali metal thiocyanate salt or atetraalkylammonium thiocyanate salt.

Suitable alkali metal thiocyanate salts include sodium, lithium andcesium thiocyanates, but potassium thiocyanate is preferred.

The compound of formula III where n is 1 is known (Wolf, E. et al., Can.J. Chem., 75:942–948, 1997) and compounds of formula III where n is 2 or3 are new compounds that can be prepared by those skilled in the art(see examples). The preferred hydroxyl protecting groups (R₅) includeorganosilyl compounds such as chosen from trialkysilyl, triphenylsilyl,phenyldialkylsilyl or alkyldiphenylsilyl group. Thetert-butyldimethylsilyl (TBDMS) group is especially preferred. Thepreferred amino protecting groups (R₆) include carbamates such alkylcarbamates, in particular the t-butyl carbamate (Boc) group, andalkylaryl carbamates. The reaction may be run with a small excess of thecompound of formula III and potassium thiocyanate (preferably 1.1–1.3equivalents).

The invention also provides compounds of formula II, where at least oneof R₁, R₂ and R₃ is fluorine.

The reaction can be run in a substantially inert solvent (preferablyethyl acetate) and at different temperatures (preferably at the solventreflux temperature). Preferred organic acids include acetic acid. Whencompounds of formula III where n signifies 1 are used, the intermediateof formula IV is then treated with a mineral acid in a suitable solventto remove the Boc amino protecting group and provide the compounds offormula I (scheme 1). Preferred mineral acids include hydrochloric acidand preferred solvents include ethyl acetate.

When compounds of formula III where n signifies 2 are used and R₄signifies hydrogen, the mixture of intermediate products of formula Vand VI is reacted with hydrochloric acid in ethyl acetate to afford thecorresponding single compounds of formula I (scheme 2); where R₄signifies alkyl (including alkyl substituted by aryl), the singleintermediate product of formula V is reacted with hydrochloric acid inethyl acetate to afford the compounds of formula I.

When compounds of formula III where n is 3 are used, the intermediate offormula VII is then treated with sodium borohydride in a suitablesolvent system followed by acetic acid to remove the pthalimido aminoprotecting group as described in the literature (Osby et al.,Tetrahedron Lett., 1984, 25(20), 2093–2096) to give the compounds offormula I (scheme 3). The compounds of formula I are obtained with goodpurity, but if preferred can be recrystallised from a suitable solvent.

For the preparation of pharmaceutical compositions of compounds offormula I, inert pharmaceutically acceptable carriers are admixed withthe active compounds. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules and capsules. A solid carrier can be oneor more substances which may also act as diluents, flavouring agents,solubilizers, lubricants, suspending agents, binders or tabletdisintegrating agents; it may also be an encapsulating material.

Preferably the pharmaceutical preparation is in unit dosage form, e.g.packaged preparation, the package containing discrete quantities ofpreparation such as packeted tablets, capsules and powders in vials orampoules.

The dosages may be varied depending on the requirement of the patient,the severity of the disease and the particular compound being employed.For convenience, the total daily dosage may be divided and administeredin portions throughout the day. It is expected that once or twice perday administration will be most suitable. Determination of the properdosage for a particular situation is within the skill of those in themedical art.

MATERIALS AND METHODS In Vitro Studies

DβH activity was evaluated by the ability to β-hydroxylate dopamine tonoradrenaline as previously described (Kojima, K., Parvez, S. andNagatsu T. 1993. Analysis of enzymes in catecholamine biosynthesis. InMethods in Neurotransmitter and Neuropeptide Research, pp. 349–380:Elsiever Science Publishers). SK-N-SH cells (ATCC HTB-11), a humanneuroblastoma derived cell line, were used as a source of human DβH.SK-N-SH cells cultured in 24 well plates were preincubated for 20 min ina reaction medium containing 200 mM sodium acetate, 30 mMN-ethylmaleimide, 5 μM copper sulphate, 0.5 mg/ml catalase aqueoussolution, 1 mM pargyline, 10 mM sodium fumarate and 20 mM ascorbic acid.Thereafter, cells were incubated for further 45 min in the reactionmedium with added increasing concentrations of dopamine (0.5 to 100 mM).During preincubation and incubation, the cells were continuously shakenand maintained at 37° C. The reaction was terminated by the addition of0.2 M perchloric acid. The acidified samples were stored at 4° C. beforeinjection into the high pressure liquid chromatograph for the assay ofnoradrenaline. In experiments conducted with the aim of studying theeffects of new DβH inhibitors on enzyme activity, test compounds (0.3 to10,000 nM) of interest were added to the preincubation and incubationsolutions; the incubation was performed in the presence of aconcentration (50 mM) of dopamine 2.5 times the corresponding K_(m)value as determined in saturation experiments.

In Vivo Studies

Male NMRI mice or Wistar rats were obtained from Harlan-Interfauna(Spain) and were kept 10 and 5 per cage respectively, under controlledenvironmental conditions (12 h light/dark cycle and room temperature22±1° C.). Food and tap water were allowed ad libitum andexperimentation was performed during daylight hours.

At time =0 h, animals were administered with either test compounds at agiven dose or vehicle (water) delivered orally via gavage. At 2, 6, 9,12, 18 and 24 h post dose, the animals were sacrificed by decapitationand heart (left atrium and left ventricle) and brain (frontal andparietal cortex) were isolated, weighed and stored in a volume of 0.2 Mperchloric acid for 12 h at 4° C. in the dark. Post incubation, theresulting supernatants were collected by centrifuge filtration ofincubates (0.2 μM/10 min/˜5000 rpm, 4° C.). Supernatants were storedfrozen at −80° C. until analysis. Quantification of dopamine andnoradrenaline in supernatants was performed by high pressure liquidchromatography with electrochemical detection.

RESULTS In Vitro Studies

Incubation of SK-N-SH cells in the presence of increasing concentrationsof dopamine resulted in a concentration-dependent formation ofnoradrenaline, yielding K_(m) (in μM) and V_(max) (in nmol mg protein⁻¹h⁻¹) values of 20.6±1.6 and 153.8±4.4, respectively. From these kineticparameters, a concentration of dopamine approaching saturation (50 mM)was chosen for use in inhibition studies. As listed in Table 1 compounds2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 19, 24, 26, 28 and 29 were found tomarkedly inhibit DβH activity. Compounds 2, 3, 4 and nepicastat 1 (thereference compound) produced a concentration-dependent decrease in theβ-hydroxylation of dopamine with IC₅₀ values in the low nM range againsthuman DβH activity (see Table 2). Compound 4 was chosen for further invivo studies, being the compound most closely related to nepicastat 1 inorder to provide conclusive evidence that the structural modificationsmade to the molecule as part of the present invention are responsiblefor the surprisingly markedly improved biological properties observed.

TABLE 1* No. Mean ± SEM 1 0.0 ± 0.3 2 1.6 ± 0.3 3 4.1 ± 0.6 4 3.3 ± 0.35 8.1 ± 0.3 6 6.9 ± 0.6 7 8.0 ± 0.1 8 9.4 ± 0.7 9 50.2 ± 1.9  10 8.2 ±0.7 11 36.7 ± 4.4  12 3.0 ± 0.5 13 94.0 ± 3.1  14 77.9 ± 2.2  15 86.1 ±2.7  16 0.0 ± 0.6 17 53.2 ± 3.9  18 94.8 ± 1.2  19 6.9 ± 0.5 20 16.8 ±4.8  21 124.8 ± 6.5  22 17.8 ± 2.1  23 54.5 ± 9.9  24 0.0 ± 1.9 25 66.0± 4.5  26 4.5 ± 1.9 27 15.5 ± 5.8  28 2.6 ± 1.6 29 2.2 ± 2.5 30 99.4 ±2.8  31 27.3 ± 0.4  *Effect of selected compounds (5 μM) on DβH activityin SK-N-SH cells. Values are quoted as % of control.

TABLE 2* Compound IC₅₀ (in nM) 2  60 (14, 250) 3  91 (56, 147) 4 105(69, 161) Nepicastat 1  36 (28, 46) *IC₅₀ values (in nM) for inhibitionof DβH in SK-N-SH cells.

In Vivo Studies Mouse

The time course experiments for compound 4 and nepicastat (1) in theheart at 100 mg/kg suggests that both compounds are long acting. Time ofmaximum effect (T_(max)) for noradrenaline tissue reduction by both 4and 1 appears to be at 9 h post-dose (FIG. 1). Thereafter, noradrenalinetissue levels recover, reaching 50% recovery of initial tissue levels at24 h.

At T_(max) (9 h after administration), both 4 and 1 reducednoradrenaline levels in a dose-dependent manner in left ventricle. Forboth 4 and 1, the maximal inhibitory effect was attained at a dose of100 mg/kg. In contrast to that found in the heart, 4 failed to affectnoradrenaline tissue levels in the brain parietal cortex, whereas 1produced a dose-dependent decrease in noradrenaline levels in this areaof the brain (FIG. 2).

Rat

As shown in the mouse, the effects of both 4 and 1 upon noradrenalinewere dependent on the dose administered and reached its maximum at 9 h(data not shown). However, as depicted in FIG. 3, the inhibitory effectsof 4 (100 mg/kg) upon noradrenaline levels in both the left atrium andthe left ventricle were more pronounced than those elicited by 1 (100mg/kg). Again, as observed in the mouse, 4 failed to affectnoradrenaline tissue levels in the brain parietal cortex and the brainfrontal cortex, whereas 1 produced a marked decrease in noradrenalinelevels in these brain areas.

It is concluded that 4, in stark contrast to nepicastat 1, exerts itsinhibitory effects upon DβH exclusively in the periphery, being devoidof inhibitory effects in the brain.

Reference is now made to the accompanying drawings, in which:

FIG. 1 is a graph showing the time-dependent decrease of noradrenalinelevels in the left ventricle of mice treated orally with 100 mg/kg of 4or nepicastat 1. Symbols are means of 5 determinations per group;vertical lines indicate S.E.M.

FIG. 2 is two graphs showing noradrenaline levels in the mouse leftventricle and brain parietal cortex 9 h after oral administration of 4or nepicastat 1. Symbols are means of 5 determinations per group;vertical lines indicate S.E.M.

FIG. 3 is four graphs showing noradrenaline levels in the rat heart(left atrium and left ventricle) and brain (frontal and parietal cortex)9 h after the oral administration of 4 or nepicastat 1. Columns aremeans of 5 determinations per group; vertical lines indicated S.E.M.

CONCLUSION

Some compounds of general formula I are very potentdopamine-β-hydroxylase inhibitors and have potentially valuablepharmaceutical properties in the treatment of some cardiovasculardisorders, where a reduction in the enzymatic hydroxylation of dopamineto noradrenaline may be of therapeutic benefit, such as hypertension andchronic heart failure. The possibility to use a long-acting DβHinhibitor with limited access to the brain (CNS), such as compound 4opens new perspectives in the treatment of hypertension and chronicheart failure by improving potency and selectivity of DβH inhibition inthe periphery.

The invention disclosed herein is exemplified by the following examplesof preparation, which should not be construed to limit the scope of thedisclosure. Alternative pathways and analogous structures may beapparent to those skilled in the art.

EXAMPLES Example 1

(R)-5-aminomethyl-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride (compound 3, Table 1)

A stirred mixture of (R)-6,8-difluorochroman-3-ylamine hydrochloride(0.22 g, 1.0 mmol),[3-(tert-butyldimethylsilanyloxy)-2-oxopropyl]carbamic acid tert-butylester (0.33 g, 1.1 mmol), potassium thiocyanate (0.11 g, 1.1 mmol) andacetic acid (0.3 mL, 5.0 mmol) in ethyl acetate (3 mL) was refluxed for2 hours, cooled to room temperature, then washed by sodium bicarbonatesolution, dried over anhydrous magnesium sulphate and evaporated invacuo. The residue was purified by the column chromatography over silicagel using ethyl acetate-petroleum ether mixture as eluent. The resultingoil (0.23 g) was dissolved in ethyl acetate (2 ml), whereupon 2M HClsolution in ethyl acetate was added (2 mL, 4 mmol) and the mixture wasstirred for 2 hours at room temperature. The precipitate was removed byfiltration and washed with ethyl acetate to give crystals of m.p. 192°C. (decomp.).

Examples 2–3

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriatechroman-3-ylamines hydrochlorides, the following compounds wereprepared:

(R)-5-aminomethyl-1-chroman-3-yl-1,3-dihydroimidazole-2-thionehydrochloride (compound 24, table 1)

(R)-5-aminomethyl-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride (compound 22, table 1)

Example 4

(R,S)-5-aminomethyl-1-(6-hydroxythiochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride

A stirred mixture of 6-hydroxythiochroman-3-ylamine hydrochloride (0.22g, 1.0 mmol), [3-(tert-butyldimethylsilanyloxy)-2-oxopropyl]carbamicacid tert-butyl ester (0.33 g, 1.1 mmol), potassium thiocyanate (0.11 g,1.1 mmol) and acetic acid (0.3 mL, 5.0 mmol) in ethyl acetate (3 mL) wasrefluxed for 2 hours, then cooled to room temperature, and washed bysodium bicarbonate solution, dried over anhydrous magnesium sulphate andevaporated in vacuo. The residue was purified by column chromatographyon silica using ethyl acetate-petroleum ether mixture as eluent. Theresulting oil (0.25 g) was dissolved in ethyl acetate (2 ml), whereupon2M HCl solution in ethyl acetate was added (2 mL, 4 mmol) and themixture was stirred for 2 hours at room temperature. The precipitate wasremoved by filtration and washed with ethyl acetate to give crystals,which decomposed without melting.

Example 5

(3,4-Dihydroxybutyl)carbamic acid tert-butyl ester

To a stirred solution of 4-amino-1,2-propanediol (2.10 g, 20 mmol) inethanol (50 mL) at room temperature was added di-tert-butyldicarbonate(4.80 g, 22 mmol) in one portion. The resulting mixture was stirred atroom temperature for two hours, then evaporated in vacuo and purified bycolumn chromatography on silica using ethyl acetate-petroleum ethermixture as eluent to afford colourless oil.

Examples 6–7

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriateN-substituted 4-amino-1,2-propanediols, the following compounds wereprepared:

(3,4-Dihydroxybutyl)methylcarbamic acid tert-butyl ester

(3,4-Dihydroxybutyl)benzylcarbamic acid tert-butyl ester

Example 8

[4-(tert-butyldimethylsilanyloxy)-3-hydroxybutyl]carbamic acidtert-butyl ester

To a stirred solution of (3,4-dihydroxybutyl)carbamic acid tert-butylester (2.60 g, 12.7 mmol), triethylamine (2.03 mL, 14.50 mmol) and4-(dimethylamino)pyridine (0.05 g, 0.4 mmol) in anhydrousdichloromethane (40 mL) at room temperature was addedtert-butyldimethylchlorosilane (2.0 g, 13.17 mmol) in one portion. Theresulting mixture was stirred at room temperature for 18 hours, washedwith water, brine and dried over anhydrous magnesium sulfate. Filtrationand concentration in vacuo gave an oil which was purified by columnchromatography on silica using ethyl acetate-petroleum ether mixture aseluent to afford a colourless oil.

Example 9–10

By the application of the above described technique and relatedprocedures known to those skilled in the art and using compounds fromexamples 6 and 7, the following compounds were prepared:

[4-(tert-butyldimethylsilanyloxy)-3-hydroxybutyl]methylcarbamic acidtert-butyl ester

[4-(tert-butyldimethylsilanyloxy)-3-hydroxybutyl]benzylcarbamic acidtert-butyl ester

Example 11

[4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butylester

To a solution of Dess-Martin periodinane (5.0 g, 11.8 mmol) in anhydrousdichloromethane (35 mL) at room temperature was added a solution of[4-(tert-butyldimethylsilanyloxy)-3-hydroxybutyl]carbamic acidtert-butyl ester (3.77 g, 11.8 mmol) in anhydrous dichloromethane. Theresulting mixture was stirred at room temperature for one hour,evaporated in vacuo to one third of the initial volume and applied to acolumn packed with silica. Elution with ethyl acetate-petroleum ethersolvent mixture afforded a colourless oil.

Example 12–13

By the application of the above described technique and relatedprocedures known to those skilled in the art and using compounds fromexamples 9 and 10, the following compounds were prepared:

[4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]methylcarbamic acidtert-butyl ester

[4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]benzylcarbamic acidtert-butyl ester.

Example 14

(S)-5-(2-aminoethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thionehydrochloride, compound 2, table 1)

A stirred mixture of (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride (0.17 g, 0.79 mmol),[4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butylester (0.28 g, 0.87 mmol), potassium thiocyanate (0.085 g, 0.85 mmol),water (0.014 mL, 0.80 mmol) and acetic acid (0.2 mL, 3.3 mmol) in ethylacetate (2 mL) was refluxed for 7 hours, cooled to the room temperature,washed by sodium bicarbonate solution and dried over anhydrous magnesiumsulphate and evaporated in vacuo. The residue was purified by columnchromatography on silica using ethyl acetate-petroleum ether mixture aseluent. The resulting oil (0.24 g) was dissolved in ethyl acetate (2ml), 2M HCl solution in ethyl acetate was added (2 mL, 4 mmol) and themixture was stirred for 2 hours at room temperature. The precipitate wasremoved by filtration and washed with ethyl acetate to give crystals,which decomposed without melting.

Example 15

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriate1,2,3,4-tetrahydronaphthalen-2-ylamines hydrochlorides, the followingcompounds were prepared:

(S)-5-(2-aminoethyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thionehydrochloride (compound 20, table 1)

Example 16

(R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride (compound 4, table 1)

A stirred mixture of (R)-6,8-difluorochroman-3-ylamine hydrochloride(1.68 g, 7.58 mmol),[4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butylester (3.13 g, 9.85 mmol), potassium thiocyanate (0.96 g, 9.85 mmol),water (0.18 mL, 10 mmol) and acetic acid (3.0 mL, 50 mmol) in ethylacetate (30 mL) was refluxed for 7 hours, cooled to room temperature,washed by sodium bicarbonate solution, dried over anhydrous magnesiumsulphate and evaporated in vacuo. The residue was purified by columnchromatography on silica using ethyl acetate-petroleum ether mixture aseluent. The resulting oil (2.15 g) was dissolved in ethyl acetate (20ml), 2M HCl solution in ethyl acetate was added (20 mL, 40 mmol) and themixture was stirred for 2 hours at room temperature. The precipitate wasremoved by filtration and washed with ethyl acetate to give crystals,which decomposed without melting.

Example 17–37

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriatechroman-3-ylamine hydrochlorides and[4-(tert-butyldimethylsilanyloxy)-3-oxobutyl]carbamic acid tert-butylesters, the compounds listed in Table 3 were prepared:

TABLE 3 Ex. Compound Ref to Table 1 17(R)-5-(2-aminoethyl)-1-chroman-3-yl-1,3-dihydroimidazole-2-thionehydrochloride Compound 12 18(R)-5-(2-aminoethyl)-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 16 hydrochloride 19(R)-5-(2-aminoethyl)-1-(8-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 21 hydrochloride 20(R)-5-(2-aminoethyl)-1-(6-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 23 hydrochloride 21(R)-5-(2-aminoethyl)-1-(8-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 19 hydrochloride 22(R)-5-(2-aminoethyl)-1-(6-fluorochroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 7 hydrochloride 23(R)-5-(2-aminoethyl)-1-(8-fluorochroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 6 hydrochloride 24(R)-5-(2-aminoethyl)-1-(6,7-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 8 hydrochloride 25(S)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 9 hydrochloride 26(R)-5-(2-aminoethyl)-1-(6,7,8-trifluorochroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 10 hydrochloride 27(R)-5-(2-aminoethyl)-1-(6-chloro-8-methoxychroman-3-yl)-1,3-dihydroimidazole-2-Compound 11 thione hydrochloride 28(R)-5-(2-aminoethyl)-1-(6-methoxy-8-chlorochroman-3-yl)-1,3-dihydroimidazole-2-Compound 13 thione hydrochloride 29(R)-5-(2-aminoethyl)-1-(6-nitrochroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 18 hydrochloride 30(R)-5-(2-aminoethyl)-1-(8-nitrochroman-3-yl)-1,3-dihydroimidazole-2-thioneCompound 17 hydrochloride 31(R)-5-(2-aminoethyl)-1-[6-(acetylamino)chroman-3-yl]-1,3-dihydroimidazole-2-Compound 14 thione hydrochloride 32(R)-5-(2-aminoethyl)-1-(6-hydroxy-7-benzylchroman-3-yl)-1,3-dihydroimidazole-2-Compound 15 thione hydrochloride 33(R)-5-(2-Benzylaminoethyl)-1-(6-methoxychroman-3-yl)-1,3-dihydroimidazole-2-Compound 25 thione hydrochloride 34(R)-5-(2-Benzylaminoethyl)-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-Compound 26 thione hydrochloride 35(R)-1-(6-Hydroxychroman-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-Compound 27 thione hydrochloride 36(R)-1-(6,8-Difluorochroman-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-Compound 28 thione hydrochloride 37(R)-1-Chroman-3-yl-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thioneCompound 29 hydrochloride

Example 38

(R,S)-5-(2-aminoethyl)-1-(6-methoxythiochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride (compound 30, table 1)

A stirred mixture of 6-methoxythiochroman-3-ylamine hydrochloride (0.12g, 0.50 mmol), [3-(tert-butyldimethylsilanyloxy)-2-oxopropyl]carbamicacid tert-butyl ester (0.17 g, 0.55 mmol), potassium thiocyanate (0.055g, 0.55 mmol), water (0.009 g, 0.50 mmol) and acetic acid (0.2 mL, 3.3mmol) in ethyl acetate (2 mL) was refluxed for 7 hours, cooled to roomtemperature, washed by sodium bicarbonate solution, dried over anhydrousmagnesium sulphate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica using ethyl acetate-petroleum ethermixture as eluent. The resulting oil (0.12 g) was dissolved in ethylacetate (1 ml), 2M HCl solution in ethyl acetate was added (1 mL, 2mmol) and the mixture was stirred for 2 hours at room temperature. Theprecipitate was removed by filtration and washed with ethyl acetate togive crystals which decomposed without melting.

Example 39

By the application of the above described technique and relatedprocedures known to those skilled in the art and using the appropriatechroman-3-ylamine hydrochlorides, the following compounds were prepared:

(R,S)-5-(2-aminoethyl)-1-(6-hydroxythiochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride (compound 31, table 1)

Example 40

2-[3-(2,2-Dimethyl[1,3]dioxolan-4-yl)propyl]isoindole-1,3-dione

To a stirred solution of 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)propylamine(1.05 g, 6.60 mmol) and carboethoxyphthalimide (1.45 g, 6.60 mmol) inacetonitrile (10 mL) at room temperature was added triethylamine (0.92mL, 6.60 mmol) in one portion and the resuting mixture was stirred atroom temperature for 18 hours, evaporated in vacuo and the residue wasdissolved in ethyl acetate (50 mL). The solution was washed with brine,10% citric acid solution and brine, then dried over anhydrous magnesiumsulfate. Filtration and concentration in vacuo gave an oil which waspurified by column chromatography on silica using ethylacetate-petroleum ether mixture as eluent to afford a colourless oil.

Example 41

2-(4,5-Dihydroxypentyl)isoindole-1,3-dione

To a stirred solution of2-[3-(2,2-dimethyl[1,3]dioxolan-4-yl)propyl]isoindole-1,3-dione (1.65 g,5.70 mmol) in THF (20 mL) at room temperature was added 2N HCl solution(15 mL, 30 mmol) in one portion and the resulting mixture was stirred atroom temperature for two hours and then evaporated in vacuo to half ofthe initial volume. The residue was saturated with NaCl and extractedwith ethyl acetate. The organic phase was dried by anhydrous magnesiumsulfate. Filtration and concentration in vacuo afforded a colourlessoil.

Example 42

By the application of the technique described in example 8 to2-(4,5-dihydroxypentyl)isoindole-1,3-dione, the following compound wasprepared:

2-[5-(tert-Butyldimethylsilanyloxy)-4-hydroxypentyl]isoindole-1,3-dione

Example 43

By the application of the technique described in example 11 to2-[5-(tert-butyldimethylsilanyloxy)-4-hydroxypentyl]isoindole-1,3-dione,the following compound was prepared:

2-[5-(tert-Butyldimethylsilanyloxy)-4-oxopentyl]isoindole-1,3-dione

Example 44

(S)-5-(3-aminopropyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thionehydrochloride (compound 5, table 1)

A stirred mixture of (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine hydrochloride (0.22 g, 1.0 mmol),2-[5-(tert-butyldimethylsilanyloxy)-4-oxopentyl]isoindole-1,3-dione(0.38 g, 1.05 mmol), potassium thiocyanate (0.11 g, 1.10 mmol), water(0.18 g, 1.0 mmol) and acetic acid (0.3 mL, 5.0 mmol) in ethyl acetate(3 mL) was refluxed for 7 hours, cooled to room temperature, washed bysodium bicarbonate solution, dried over anhydrous magnesium sulphate andevaporated in vacuo. The residue was purified by column chromatographyon silica using ethyl acetate-petroleum ether mixture as eluent. Theresulting oil (0.18 g) was dissolved in a mixture of isopropanol (5 mL)and THF (2 mL). Water (0.8 mL) and sodium borohydride (0.066 g, 1.74mmol) were added at room temperature and the mixture was stirred for 1.5hours. Acetic acid (0.6 ml, 10 mmol) was added and the solution wasrefluxed for two hours then evaporated in vacuo to dryness. The residuewas taken up into acetone, the solid was filtered off, and the filtratewas acidified with 2N HCl solution in ethyl acetate. The precipitate wascollected and washed with acetone to afford crystals, which decomposedwithout melting.

Example 45

(R)-5-(3-aminopropyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride

A stirred mixture of (R)-6,8-difluorochroman-3-ylamine hydrochloride(0.11 g, 0.50 mmol),2-[5-(tert-Butyldimethylsilanyloxy)-4-oxopentyl]isoindole-1,3-dione(0.19 g, 0.55 mmol), potassium thiocyanate (0.055 g, 0.55 mmol), water(0.009 g, 0.50 mmol) and acetic acid (0.15 mL, 2.5 mmol) in ethylacetate (1.5 mL) was refluxed for 7 hours, cooled to the roomtemperature, washed by sodium bicarbonate solution, dried over anhydrousmagnesium sulphate and evaporated in vacuo. The residue was purified bycolumn chromatography on silica using ethyl acetate-petroleum ethermixture as eluent. The resulting oil (0.10 g) was dissolved in themixture of isopropanol (2.5 mL) and THF (1 mL). Water (0.4 mL) andsodium borohydride (0.038 g, 1.0 mmol) were added at room temperatureand the mixture was stirred for 1.5 hours. Acetic acid (0.3 ml, 5 mmoj)was added and the solution was refluxed for two hours and evaporated invacuo to dryness. The residue was taken up in acetone, the solid wasfiltered off, and the filtrate was acidified with 2N HCl solution inethyl acetate. The precipitate was collected and washed with acetone toafford crystals, which decomposed without melting.

Example 46

(R,S)-5-(3-aminopropyl)-1-(6-hydroxythiochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride

A stirred mixture of 6-hydroxythiochroman-3-ylamine hydrochloride (0.22g, 1.0 mmol),2-[5-(tert-Butyldimethylsilanyloxy)-4-oxopentyl]isoindole-1,3-dione(0.38 g, 1.05 mmol), potassium thiocyanate (0.11 g, 1.10 mmol), water(0.18 g, 1.0 mmol) and acetic acid (0.3 mL, 5.0 mmol) in ethyl acetate(3 mL) was refluxed for 7 hours, cooled to room temperature, washed bysodium bicarbonate solution, dried over anhydrous magnesium sulphate andevaporated in vacuo. The residue was purified by column chromatographyon silica using ethyl acetate-petroleum ether mixture as eluent. Theresulting oil (0.17 g) was dissolved in the mixture of isopropanol (5mL) and THF (2 mL). Water (0.8 mL) and sodium borohydride (0.066 g, 1.74mmol) were added at room temperature and the mixture was stirred for 1.5hours. Acetic acid (0.6 ml, 10 mmoj) was added and the solution wasrefluxed for two hours and evaporated in vacuo to dryness. The residuewas taken up into acetone, the solid was filtered off and the filtratewas acidified with 2N HCl solution in ethyl acetate. The precipitate wascollected and washed with acetone to afford crystals, which decomposedwithout melting.

1. A compound of Formula I:

where R₁, R₂ and R₃ are the same or different and signify hydrogens,halogens, alkyl groups, alkyloxy groups, hydroxy groups, nitro groups,amino groups, alkylcarbonylamino groups, alkylamino groups ordialkylamino groups; R₄ signifies hydrogen, an alkyl group or analkylaryl group; X signifies CH₂, an oxygen atom or a sulphur atom; n is1, 2 or 3, with the proviso that when n is 1, X is not CH₂; and theindividual (R)- and (S)-enantiomers or mixtures of enantiomers andpharmaceutically acceptable salts thereof; wherein the term alkyl meanshydrocarbon chains, straight or branched, containing from one to sixcarbon atoms, optionally substituted by aryl groups, alkoxy groups,halogen groups, alkoxycarbonyl groups or hydroxycarbonyl groups; theterm aryl means a phenyl or naphthyl group, optionally substituted by analkyloxy group, halogen or nitro group; and the term halogen meansfluorine, chlorine, bromine or iodine.
 2. A compound according to claim1 selected from the group consisting of:(S)-5-(2-aminoethyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thionehydrochloride; dihydroimidazole-2-thione hydrochloride;(R)-5-(2-benzylaminoethyl)-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride;(R)-1-(6-hydroxychroman-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thionehydrochloride;(R)-1-(6,8-difluorochroman-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thionehydrochloride; and(R)-1-chroman-3-yl-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thionehydrochloride.
 3. A process for the preparation of the individual (R)-and (S)-enantiomers or mixtures of enantiomers and pharmaceuticallyacceptable salts of a compound according to claim 1, the processcomprising: reacting individual (R)- or (S)-enantiomers or mixtures ofenantiomers of a compound of Formula II

 where X is CH₂, oxygen or sulphur; R₁, R₂ and R₃ are the same ordifferent and signify hydrogens, halogens, alkyl groups, alkyloxygroups, hydroxy groups, nitro groups, alkylcarbonylamino groups,alkylamino groups or dialkylamino groups; with a compound of Formula III

 where n signifies 1, 2 or 3; with the proviso that when n is 1 or 2, R₄signifies hydrogen or an alkyl group, R₅ signifies a hydroxyl protectinggroup and R₆ signifies an amino protecting group, but when n is 3, R₅ isdefined as above but R₄ and R₆ taken together represent a phthalimidogroup; and with a water soluble thiocyanate salt in the presence of anorganic acid in a substantially inert solvent; and subsequentlydeprotecting the intermediate products of Formulas IV–VII:

 wherein the water soluble thiocyanate salt is an alkali metalthiocyanate salt or a tetraalkylammonium thiocyanate salt, and whereinthe term alkyl means a hydrocarbon chain, straight or branched,containing from one to six carbon atoms, optionally substituted by oneor more aryl groups, alkoxy groups, halogens, alkoxycarbonyl groups orhydroxycarbonyl groups; the term aryl means a phenyl or naphthyl group,optionally substituted by an alkyloxy group, halogen or nitro group; andthe term halogen means fluorine, chlorine, bromine or iodine.
 4. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 1 in combination with apharmaceutically effective carrier.
 5. A method of inhibitingdopamine-β-hydroxylase in treating a disorder where a reduction in thehydroxylation of dopamine to noradrenaline is of therapeutic benefit,comprising administering a compound according to claim 1 to a patient inneed thereof.
 6. The method according to claim 5 wherein the disorder isselected from the group consisting of hypertension and chronic heartfailure.
 7. A compound according to claim 1 selected from the groupconsisting of:(S)-5-(2-aminoethyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-chroman-3-yl-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(8-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(8-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6-fluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(8-fluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6,7-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;(S)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6,7,8-trifluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6-chloro-8-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6-methoxy-8-chlorochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6-nitrochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(8-nitrochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-[6-(acetylamino)chroman-3-yl]-1,3-dihydroimidazole-2-thione;(R)-5-aminomethyl-1-chroman-3-yl-1,3-dihydroimidazole-2-thione;(R)-5-aminomethyl-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-aminoethyl)-1-(6-hydroxy-7-benzylchroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(3-aminopropyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione;(S)-5-(3-aminopropyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione;(R,S)-5-(2-aminoethyl)-1-(6-hydroxythiochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R,S)-5-(2-aminoethyl)-1-(6-methoxythiochroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-benzylaminoethyl)-1-(6-methoxychroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-5-(2-benzylaminoethyl)-1-(6-hydroxychroman-3-yl)-1,3-dihydroimidazole-2-thione;(R)-1-(6-hydroxychroman-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thione;(R)-1-(6,8-difluorochroman-3-yl)-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thione;and(R)-1-chroman-3-yl-5-(2-methylaminoethyl)-1,3-dihydroimidazole-2-thione,and pharmaceutically acceptable salts thereof.
 8. A pharmaceuticalcomposition comprising(R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thioneor a pharmaceutically acceptable salt thereof.
 9. The pharmaceuticalcomposition according to claim 8 wherein the pharmaceutically acceptablesalt is(R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride.
 10. A pharmaceutical composition comprising(S)-5-(2-aminoethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thioneor a pharmaceutically acceptable salt thereof.
 11. The pharmaceuticalcomposition according to claim 10 wherein the pharmaceuticallyacceptable salt is(S)-5-(2-aminoethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thionehydrochloride.
 12. A pharmaceutical composition comprising(R)-5-aminomethyl-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thioneor a pharmaceutically acceptable salt thereof.
 13. The pharmaceuticalcomposition according to claim 12 wherein the pharmaceuticallyacceptable salt is(R)-5-aminomethyl-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thionehydrochloride.
 14. The compound according to claim 1 wherein n is
 1. 15.The compound according to claim 1 wherein n is
 2. 16. The compoundaccording to claim 1 wherein n is
 3. 17. The compound according to claim1 wherein X is oxygen.
 18. The compound according to claim 1 wherein Xis CH₂.
 19. The compound according to claim 1 wherein one of R₁, R₂ andR₃ signifies hydrogen, and the remaining two of R₁, R₂ and R₃ signifyfluorine.